PROFESSIONAL AFFILIATIONS:

Research Interests:

My research focuses on defining the role of the complement in the pathogenesis of human diseases such as cancer, virus infection, and cardiovascular diseases. I have a broad background in medicine, molecular and cellular biology, cancer biology, cardiovascular biology and immunology. I have generated following mouse models: 1) mouse CD59 knockout mice; and 2) human CD59 (hCD59) transgenic mice expressing hCD59 only in mouse erythrocytes or only in mouse endothelial and circulating cells. CD59 is a critical complement regulator for restricting complement membrane attack complex (MAC). My lab also developed a potent and specific hCD59 inhibitor, rll Yd4.

1) Development of therapeutic anti-hCD59 inhibitor for HIV and Ab-based cancer therapy

Recognizing that the up-regulation of CD59 in cancer cells or HIV-infected cells is one of major reasons for their escape from complement-dependent cytolysis (CDC), I focus on developing hCD59 inhibitor for cancer and HIV therapy. lntermedilysin (IL Y), a cytolytic pore-forming toxin secreted by Streptococcus intermedius, lyses only human cells due to its receptor specificity for hCD59. My lab used hCD59 transgenic mice to confirm the finding that IL Y binds only to hCD59 in vivo. Domain 4 of IL Y binds to AA42-58 region in hCD59, which also participate in the binding to C8 and C9. I demonstrated that the recombinant protein (114AA) derived from the IL Y domain 4 (rll Yd4) specifically block hCD59 function and potentiate antibody-mediated CDC effect on cancer cells and inhibit human xenograft tumor growth. In addition, rll Yd4 also potentiates endogenous anti-HIV antibody-mediated complement-dependent virolysis. Importantly, no overt toxicity was observed when rll Y4 was administered to mice, even when mice are expressing hCD59 on red cells. Objective of this project is to develop the anti-hCD59 inhibitor for cancer and viral therapy and define the role of complement in immune-cancer therapy and pathogenesis of HIV infection.

2) Role of complement system in the pathogenesis of atherosclerosis and aneurysm

Extensive evidence obtained from the histological studies of human atherosclerosis and aneurysm indicate that complement (C), a key mediator of inflammation and immune responses, may play a critical role in atherogenesis and aneurysm, immune and inflammatory diseases. By the utilization of the knockout and transgenic mice together with biochemical approaches, my lab has demonstrated the protective role of CD59 in atherosclerosis and aneurysm and established the critical role of MAC in the development of these diseases in vivo. We are working on defining the underlying molecular and cellular mechanisms by which MAC contributes to the pathogenesis of atherosclerosis and aneurysm and developing a novel approach for the treatment/prevention of atherosclerosis or even advanced atherosclerosis as well as aneurysm.

3) Development of a universal cell ablation model and studies of the pathogenesis of hemolysis-associated pulmonary hypertension

Conditional and targeted cell ablation is fast becoming a powerful approach for studying cellular functions and tissue regeneration in vivo. Taking advantage of the exclusive IL Y interaction with hCD59, I have developed a novel tool to investigate the role of specific cells in the pathogenesis of human diseases. IL Y administration to the transgenic mice expressing hCD59 in specific cells can be used to generate this cell ablation model, in which IL Y specifically damages hCD59-expressing cells in the mice. We can utilize this concept to develop a new cell ablation model to study the functions of different cell types under physiologic and patho-physiologic conditions including cell differentiation and tissue development in many species. I have established multiple collaborations with Scientists in USA to further utilize this approach for their research projects in many species.

Specifically, I have developed a unique hemolytic anemia model, in which IL Y exclusively lyses erythrocytes transgenically expressing hCD59 (ThCD59RBC mice). Using this model, I investigated the pathogenesis of hemolytic anemia-associated pulmonary hypertension and sudden death. I demonstrated that the lethality of acute intravascular hemolysis in the models results from a sudden increase in pulmonary pressure likely a consequence of the reduced bioavailability of nitric oxide (NO) and resulting pulmonary vasoconstriction and platelet activation. I am utilizing this unique hemolytic mouse model to define the pathogenesis of hemolysis-associated pulmonary hypertension and sudden death and to test novel therapeutics for the treatment/prevention of the hemolysisassociated complications in this unique hemolysis model.